Association of SOX11 Polymorphisms in distal 3'UTR with Susceptibility for Schizophrenia

J Clin Lab Anal. 2020 Aug;34(8):e23306. doi: 10.1002/jcla.23306. Epub 2020 Mar 23.

Abstract

Background: Diverse and circumstantial evidence suggests that schizophrenia is a neurodevelopmental disorder. Genes contributing to neurodevelopment may be potential candidates for schizophrenia. The human SOX11 gene is a member of the developmentally essential SOX (Sry-related HMG box) transcription factor gene family and mapped to chromosome 2p, a potential candidate region for schizophrenia.

Methods: Our previous genome-wide association study (GWAS) implicated an involvement of SOX11 with schizophrenia in a Chinese Han population. To further investigate the association between SOX11 polymorphisms and schizophrenia, we performed an independent replication case-control association study in a sample including 768 cases and 1348 controls.

Results: After Bonferroni correction, four SNPs in SOX11 distal 3'UTR significantly associated with schizophrenia in the allele frequencies: rs16864067 (allelic P = .0022), rs12478711 (allelic P = .0009), rs2564045 (allelic P = .0027), and rs2252087 (allelic P = .0025). The haplotype analysis of the selected SNPs showed different haplotype frequencies for two blocks (rs4371338-rs7596062-rs16864067-rs12478711 and rs2564045-rs2252087-rs2564055-rs1366733) between cases and controls. Further luciferase assay and electrophoretic mobility shift assay (EMSA) revealed the schizophrenia-associated SOX11 SNPs may influence SOX11 gene expression, and the risk and non-risk alleles may have different affinity to certain transcription factors and can recruit divergent factors.

Conclusions: Our results suggest SOX11 as a susceptibility gene for schizophrenia, and SOX11 polymorphisms and haplotypes in the distal 3'UTR of the gene might modulate transcriptional activity by serving as cis-regulatory elements and recruiting transcriptional activators or repressors. Also, these SNPs may potentiate as diagnostic markers for the disease.

Keywords: SOX11; association; neurodevelopment; schizophrenia; single-nucleotide polymorphism (SNP).

MeSH terms

  • 3' Untranslated Regions / genetics*
  • Adolescent
  • Adult
  • Asian People / genetics
  • Case-Control Studies
  • Cell Line, Tumor
  • China
  • Female
  • Genetic Predisposition to Disease / genetics*
  • Genome-Wide Association Study
  • Humans
  • Linkage Disequilibrium
  • Male
  • Polymorphism, Single Nucleotide / genetics*
  • SOXC Transcription Factors / genetics*
  • Schizophrenia / genetics*
  • Young Adult

Substances

  • 3' Untranslated Regions
  • SOX11 protein, human
  • SOXC Transcription Factors